When the Process Becomes the Product: Single-Use Technology and the Next Biomanufacturing Paradigm

The modern biopharmaceutical industry has developed and grown over the past 35 years to a mature industry. From its starting point, marked by the generation of the first hybridoma cell line in 1975, followed by the development of molecular biology methods for the manipulation of DNA between 1980 and 2000, it is now common practice to manipulate the genome of cell lines to produce specific antibodies or therapeutic proteins and to manipulate the genome of viruses to produce safe vaccines (1, 2).

These new technologies have formed the basis for the development of new drugs produced by biotechnological methods, which have brought unprecedented economical success to the rising biopharmaceutical industry. This success is illustrated by the fact that it is forecasted that in 2014, eight out of the ten top-selling drugs (more than $1 billion cash flow) will be biopharmaceuticals (3). Today, some of these biopharmaceuticals are manufactured at the ton scale.

This success was made possible not only by new technologies, but also by the fact the engineers were able to design and build specialized equipment and facilities that fulfill the specific biopharmaceutical industry requirements for sterility, containment, and segregation at large volumes

At the beginning, traditional stainless-steel equipment stemming from chemical engineering was successfully adapted to biotechnology. The equipment was continuously improved and fine-tuned. The major improvements of chemical engineering were, however, achieved in automation and control as a consequence of the digital revolution.

The low yields achieved with the first biopharmaceutical manufacturing processes primed the construction of ever-larger equipment and facilities to achieve economy of scale while satisfying increasing demand. The largest bioreactor used for mammalian-cell cultivation has a working volume of 25,000 L. In bacterial fermentation, even larger bioreactors up to working volumes of 100,000 L have been developed.

The combination of large liquid volumes stemming from the low-yield production step with low-capacity purification methods, such as chromatography, resulted in large manufacturing facilities that integrated huge liquid-handling capabilities to operate bioreactor production and multiple purification steps. The advent of monoclonal antibodies also enabled a standardization of the process architecture and steps, further enabling the concept of standardization of distributed manufacturing facilities.

Furthermore, the cleaning and sterilization of all liquid-handling capabilities, which has to be executed with the equipment in place, requires huge capacity for the generation of water for injection (WFI) and clean steam, as well as a highly complex piping system to and from the points of use at the equipment. Table I lists key parameters of systems and facility elements for a traditional stainless-steel manufacturing facility and their single-use counterparts.

It is, therefore, not surprising that the construction of a manufacturing facility consisting of six bioreactors of 10,000 L or more and two entire purification trains requires four to five years. This estimate excludes the embedding and validation of the manufacturing process in the new facility, for a total capital expenditure (CAPEX) of more than $450 million.

Four to five years in biotech can be an eternity: by the time the facility is ready for use, there is a significant chance that the product has failed in the clinic or the process has changed dramatically, rendering the finished facility obsolete.

The routine operation of such a facility requires approximately 250 full-time employees (FTEs) for production, maintenance, and quality control (QC) because of the complicated equipment and layout, the significant number of utilities, the quality control of the facility and the utilities, and the utilization of low-capacity manufacturing technologies.

Hence, the combination of traditional stainless-steel-based technologies, complicated facility layouts, and low-yield manufacturing processes have resulted in high depreciation and operation expenditures (OPEX), which have a significant effect on the economics of business cases for new drugs and on competitiveness in general.

In the past, this cost structure was the reason why only large biopharmaceutical companies were able to build large traditional biopharmaceutical manufacturing facilities and maintain the required staff to operate these facilities. Furthermore, the economics of manufacturing in these traditional facilities were biased by the fact the biopharmaceutical drugs were, and are, sold with a significant upside (up to 90% margin), leaving the cost of goods sold (COGS) as negligible.

With the first biopharmaceutical drugs losing patent protection, the advent of biosimilar drugs, the rarefication of obvious new blockbuster drugs, and smaller markets and revenue, the biopharmaceutical industry is currently undergoing a major paradigm shift. This shift is accelerated by the development of alternative technologies to traditional chemical engineering and the rethinking of process architecture, technologies, and manufacturing facility layouts.